P389: METHOTREXATE NEUROTOXICITY IN ADULT ALL
Authors: Hannah Levavi, Andre Khazak, Orrin Pail, Kyle Farina, Marina Kremyanskaya, John Mascarenhas, Michal Bar-Natan
Journal: HemaSphere (2023)

Background: Methotrexate (MTX) neurotoxicity (NT) is severe acute or subacute central NT with potential long-term neurologic sequelae that is associated with intrathecal (IT) or intravenous (IV) administration of methotrexate chemotherapy. It is characterized by stroke-like focal neurologic deficits, seizures, speech disturbance and encephalopathy. This adverse event (AE) is estimated to occur in 3-7% of children treated with ALL, but with some reports of rates as high as 18%. Most of the information available about the incidence, presentation and ramifications of MTX neurotoxicity, are confined to the pediatric literature. Aims: This study aims to characterize MTX NT in adults with ALL. Methods: We retrospectively reviewed 172 patients with ALL and mixed phenotype acute leukemia (MPAL) age 18-65 at diagnosis and treated with regimens containing IV and/or IT MTX at The Mount Sinai Hospital between 1/1/2011 and 12/31/2022. Demographic data, disease specific characteristics, treatment regimens, treatment responses and laboratory data were collected. Patients were defined as having MTX NT if they met the 2016 Ponte di Legno toxicity working group definition of "Methotrexate-related stroke-like syndrome" (Schmiegelow, 2016). Fisher's exact test was used to assess relationships between patient-factors and MTX toxicity. Results: Of the 172 patients included in the analysis, 7.6% (13/172) developed signs and symptoms of MTX NT during their ALL treatment. One of these patients had NT on MTX re-challenge, for a total of 14 instances of MTX neurotoxicity. Baseline characteristics for patients who experienced MTX NT compared to those who did not are available in Table 1. Both sexes were equally affected (7 male and 6 female), and sex distribution was similar to those who did not experience NT. Median age at the time of the event was 38 (19 – 62) years. More patients were Hispanic or Latino in the NT group compared to the patients who did not experience NT, though this difference did not meet statistical significance (53.8% v. 27.0%, p = 0.0559). 4 of 11 patients for whom CNS disease status was available had evidence of leukemic CNS involvement at the time of neurotoxicity. In 5/14 instances (35.7%), neurologic symptoms developed after receiving both IT and IV MTX within the preceding 3 weeks, in 7 instances (50%) the patient received only IT MTX, in 1 instance (7.1%) the patient had received only IV MTX, and in 1 instance (7.1%) the type of MTX received was unknown. Symptoms occurred a median of 8 days (0 – 14) from IT MTX treatment and 14 days from IV MTX (0 - 21). Neurologic symptoms included asymmetric extremity weakness (n = 5), bilateral extremity weakness (n = 1), movement disorder (n = 1), aphasia (n = 3), dysarthria (n = 2), encephalopathy (n = 1), visual disturbances (n = 2), paresthesias (n = 2) and facial droop (n = 1). Symptoms resolved completely in 11/13 (84.6%) of patients, and resolved partially in the remaining 2 patients (15.4%). Median time to resolution of symptoms was 2 days (0 – 6 days). Summary/Conclusion: To our knowledge, this is the largest retrospective review of MTX neurotoxicity in adult patients with ALL. We demonstrate here that the incidence of MTX NT in adults is similar to that in the pediatric population, with trend to be more prevalent in Hispanic population. It can present with a wide range of neurologic findings, and usually resolves relatively quickly. Further studies are needed to elucidate patient- and treatment-related factors that contribute to the risk for this AE, and the effects of MTX neurotoxicity on disease outcomes. Table 1Keywords: Chemotherapy toxicity, Methotrexate, Acute lymphoblastic leukemia